Sleep Disordered Breathing, Obesity and Pregnancy Study (SOAP) (SOAP)

National Heart, Lung, and Blood Institute (NHLBI), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

The purpose of this study is to better understand how sleep apnea, a common sleep disorder in which a person has one or more pauses in breathing or shallow breaths while sleeping, may affect pregnancy and to determine the effect of Continuous Positive Airway Pressure (CPAP), a treatment that uses mild air pressure to keep the airways open during sleep, for pregnant women with sleep apnea.

Emerging data support a link between sleep disordered breathing (SDB) and adverse pregnancy outcomes, particularly preeclampsia. Furthermore, SDB, which is characterized by intermittent nocturnal hypoxia-reoxygenation as well as sleep disruption, results in endothelial dysfunction and metabolic dysregulation, the same biological pathways that have been associated with adverse pregnancy outcomes. Obesity is a well-known risk factor for both adverse pregnancy outcomes and SDB, and has been associated with the same aforementioned biological aberrations. Therefore, obesity complicates the definition of a causal relationship between SDB and pregnancy outcomes. While some classic cardiovascular risk factors (prehypertension) are certainly relevant in pregnancy, there are also well-established risk factors that are unique to pregnancy (uterine vascular stiffness, placental angiogenic factors). The interplay between SDB, obesity and these unique cardiovascular risk factors remains undefined, and this proposal aims to address this knowledge gap. Without this data, our ability to understand how we can mitigate these risks through the use of therapeutic interventions for SDB, such as CPAP (continuous positive airway pressure), is compromised. To further address this knowledge gap, we will make use of the placenta's ability to accumulate evidence of damage over time and provide a record of maternal vascular health throughout gestation. Numerous placental lesions deriving from maternal vascular disease have been identified and can be readily detected on placental pathology. These lesions can provide a measure of the severity of hypoxic stress experienced by the fetus during gestation. The investigators' central hypothesis is that SDB is an effect modifier that increases maternal cardiovascular risk and placental hypoxic injury in obese pregnant women, and that CPAP treatment during pregnancy will result in an improved cardiovascular risk and placental profile. To test this hypothesis the investigaotrs will identify a cohort of obese women both with and without SDB. The investigators will examine SDB's impact on maternal vascular stiffness (uterine artery Doppler), angiogenesis (pregnancy specific angiogenic factors e.g., sFLT-1) and metabolism (insulin resistance) across pregnancy (Aim 1). The investigators will perform a randomized controlled trial of autotitrating- CPAP verses sham-CPAP in pregnancy to examine the impact of CPAP treatment during pregnancy on cardiovascular risk (Aim 2) and will explore the interplay between SDB, CPAP and evidence of maternal vascular disease and chronic fetal hypoxia by evaluating the placental profile of obese women with and without SDB (Aim 3).

CPAP is a device that has a mask worn over the nose that is attached to a device that provides positive airway pressure. CPAP is worn while sleeping, it splints open the airway and prevents apneas (cessation of breathing) and hypopneas (reduced airflow while breathing).

The uterine artery was located using color doppler imaging by placing the ultrasound probe in the right or left iliac fossa in the sagittal plane. The uterine artery was then identified where it crosses the external iliac artery. Doppler waveform was obtained using a sampling gate encompassing the width of the main uterine artery at an angle of insonation of <30 degrees if possible. The PI was calculated using the formula: maximum-minimum velocity/mean velocity.

sFlt-1 is a splice variant of vascular endothelial growth receptor (VEGF) with antiangiogenic properties that is upregulated in preeclampsia. PlGF is an angiogenic cytokine that is highly expressed in the placenta. Low levels have been associated with preeclampsia.

Homeostasis Model Assessment of Insulin Resistance (HOMA-IR)-Blood Measurement of Glucose and Insulin

Insulin resistance was calculated using the homeostatic model assessment for insulin resistance (HOMA-IR, fasting insulin (µU/mL) x fasting glucose (mmol/L) /22.5)

The uterine artery was located using color doppler imaging by placing the ultrasound probe in the right or left iliac fossa in the sagittal plane. The uterine artery was then identified where it crosses the external iliac artery. Doppler waveform was obtained using a sampling gate encompassing the width of the main uterine artery at an angle of insonation of <30 degrees if possible. The PI was calculated using the formula: maximum-minimum velocity/mean velocity.

sFlt-1 is a splice variant of vascular endothelial growth receptor (VEGF) with antiangiogenic properties that is upregulated in preeclampsia. PlGF is an angiogenic cytokine that is highly expressed in the placenta. Low levels have been associated with preeclampsia.

Homeostasis Model Assessment of Insulin Resistance (HOMA-IR)-Blood Measurement of Glucose and Insulin

Insulin resistance was calculated using the homeostatic model assessment for insulin resistance (HOMA-IR, fasting insulin (µU/mL) x fasting glucose (mmol/L) /22.5)

Preeclampsia, Gestational diabetes, Gestational age at delivery, Indication for delivery, Birthweight, Cord gases

Endoglin is a coreceptor for transforming growth factor beta-1 and beta-3 expressed on syncytiotrophoblasts

Endoglin is a coreceptor for transforming growth factor beta-1 and beta-3 expressed on syncytiotrophoblasts

Inclusion Criteria: women between 14 0/7 and 20 6/7 weeks gestation at the time of their initial PSG assessment. Pregnancy and current BMI >=30 Self-reported frequent snoring (>=3x/week over past month) or self-reported non-snorer. Exclusion Criteria: diagnosis of pregestational diabetes. self-report a history of sleep apena and who are using or were receommended by a physican to use a PAP device already twins

Onslow ML, Wolsk J, Wisniewski S, Patel S, Gallaher M, Hubel C, Cashmere DJ, Facco FL. The association between sleep-disordered breathing and maternal endothelial and metabolic markers in pregnancies complicated by obesity. J Clin Sleep Med. 2023 Jan 1;19(1):97-109. doi: 10.5664/jcsm.10254.